Millions of U.S. adults and adolescents do not receive key evidence-based preventive care services. Rural populations are especially disadvantaged with multiple healthcare disparities, resulting in lower rates of primary and secondary cancer prevention interventions. The objective of this project is to implement and evaluate the effectiveness of a sophisticated Web-based, electronic health record (EHR)-linked clinical decision support (CDS) system designed to improve primary and secondary cancer preventive care. To achieve this objective, we link EHR data to evidence-based cancer prevention algorithms in a secure Web site to: (a) identify at the point of care all eligible patients not up o date on their cancer prevention interventions; and (b) present to both patient and primary care provider (PCP) and/or a key member of the primary care team, certified medical assistant (CMA), appropriate evidence-based primary cancer prevention interventions and cancer screening options at the point of care. The Cancer Prevention-CDS will focus on breast cancer screening in women aged 50-74, colorectal cancer screening for both sexes aged 50-75, cervical cancer screening for women aged 21-65, human papilloma virus (HPV) vaccination for both sexes aged 11-26, and referrals for weight management and smoking cessation in all adults aged 18 and older. Effectiveness is assessed by cluster-randomizing 30 primary care clinics with roughly 285 PCPs and 153,000 study-eligible patients into one of three experimental conditions: Group 1: PCP-focused CDS intervention in which the PCP triggers use of the CDS system and engages patients in appropriate cancer prevention strategies. Group 2: CMA-focused CDS intervention in which the CMA triggers use of the CDS system and interacts with the patient to engage them in appropriate cancer prevention strategies before seeing their PCP, who will approve or discuss the plan with their patient. Group 3 clinics provide usual care with no intervention-related activity related to cancer prevention. With 10 clinics, 95 PCPs, and 51,000 potentially eligible patients per study arm, this study will formally test the hypothesis tht Groups 1 and 2 are superior to Group 3 over an 18-month follow-up period with respect to: (a) significantly higher rates of appropriate screening for breast, cervix, and colorectal cancer, as defined by the United States Preventive Services Task Force; and (b) significantly higher rates of human papillomavirus (HPV) vaccination in males and females aged 11-26 years. We further posit that Groups 1 and 2 will have higher short-term health care costs but better long-term cost-effectiveness than Group 3. The Consolidated Framework for Implementation Research (CFIR) and RE-AIM conceptual frameworks will be used to guide implementation planning, organization, conduct, and impact evaluation of the intervention in a large rural healthcare system. This project will engage a rural population with substantial healthcare disparities and gaps in the receipt of primary and secondary cancer prevention. Results will advance dissemination and implementation research methods that can reduce health disparities and improve healthcare for millions in medically underserved areas.